Clinical characteristics: Collagen type VI-related disorders represent a continuum of overlapping phenotypes with Bethlem myopathy at the mild end, Ullrich congenital muscular dystrophy (CMD) at the severe end, and two rare, less well-defined disorders – autosomal dominant limb-girdle muscular dystrophy and autosomal recessive myosclerosis myopathy – in between. Although Bethlem myopathy and Ullrich CMD were defined long before their molecular basis was known, they remain useful for clarification of prognosis and management. Bethlem myopathy, characterized by the combination of proximal muscle weakness and variable contractures, affects most frequently the long finger flexors, elbows, and ankles. Onset may be prenatal (characterized by decreased fetal movements), neonatal (hypotonia or torticollis), in early childhood (delayed motor milestones, muscle weakness, and contractures), or in adulthood (proximal weakness and Achilles tendon or long finger flexor contractures). Because of slow progression, more than two thirds of affected individuals over age 50 years rely on supportive means for outdoor mobility. Respiratory involvement is rare and appears to be related to more severe muscle weakness in later life. Ullrich CMD is characterized by congenital weakness and hypotonia, proximal joint contractures, and striking hyperlaxity of distal joints. Some affected children acquire the ability to walk independently; however, progression of the disease often results in later loss of ambulation. Early and severe respiratory involvement may require ventilatory support in the first or second decade of life.
Diagnosis/testing: Diagnosis depends on typical clinical features; normal or only mildly elevated serum creatine kinase concentration; suggestive pattern on muscle magnetic resonance imaging (MRI); muscle biopsy with collagen VI immunolabeling (for suspected Ullrich CMD) or skin biopsy and dermal fibroblast culture with collagen VI immunolabeling (for suspected Bethlem myopathy); and molecular genetic testing of COL6A1, COL6A2, and COL6A3, the three genes encoding the three collagen VI peptide chains.
Management: Treatment of manifestations: As needed based on clinical findings: physiotherapy regarding stretching exercises, splinting, and mobility aids; orthopedic assessment if surgery for Achilles tendon contractures is being considered; therapy for scoliosis. Respiratory: evaluation for nocturnal hypoventilation; prophylaxis of chest infections with vaccination and physiotherapy; aggressive treatment of pulmonary infections. Nutrition: assessment of nutritional status and growth; management of feeding difficulties. Surveillance: Routine assessment of: muscle weakness, scoliosis, joint contractures, and mobility; respiratory function; and nutritional status.
Genetic counseling: The Bethlem myopathy phenotype is usually inherited in an autosomal dominant manner and the UMD phenotype is usually inherited in an autosomal recessive manner; however, exceptions occur. In the few cases reported to date, it appears that autosomal dominant limb-girdle muscular dystrophy is inherited in an autosomal dominant manner and the myosclerosis myopathy phenotype is inherited in an autosomal recessive manner. Carrier testing for autosomal recessive collagen VI-related disorders and prenatal testing are possible if the pathogenic variants have been identified in an affected family member.
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